A great deal of research is currently underway to develop treatments and cures for viral infections in humans and in animals. Notably the incidence of AIDS and AIDS related complex (ARC) in humans is increasing at an alarming rate. The five year survival rate for those with AIDS is dispiriting and AIDS patients, whose immune systems have been seriously impaired by the infection, suffer from numerous opportunistic infections including Kaposi's sarcoma and Pneumocystis carninii pneumonia. No cure for AIDS is known and current treatments are largely without adequate proof of efficacy and have numerous untoward side effects. Fear of the disease has resulted in social ostracism of and discrimination against those having or suspected of having the disease.
It has been disclosed in South African Patent 90/0094, issued Oct. 31, 1990, that a purified form of heparin, a sulfated polysaccharide, binds through interactions to a viral protein which is responsible for cell recognition and provides limited inhibition of host cell infection. However, heparin causes some side effects, notably hemorrhage and increased clot formation time as well as thrombocytopenia. Use of heparin is contraindicated in patients who are actively bleeding, or have hemophilia, purpura, thrombocytopenia, intracranial hemorrhage, bacterial endocarditis, active tuberculosis, increased capillary permeability, ulcerative lesions of the gastrointestinal tract, severe hypertension, threatened abortion or visceral carcinoma. The contraindication for use by hemophiliacs is particularly of concern because many such individuals are now HIV positive.
It has long been recognized that certain synthetic, water-soluble polymers exhibit a broad spectrum of biological activity [R. M. Ottenbrite in "Biological Activities of Polymers", Amer. Chem. Soc. Symp. Ser., No. 182, pp. 205-220, eds. C. E. Carraher and C. G. Gebelein (1982)]. Although the mechanism of action of such water-soluble polymers is unknown, one postulate is that the polymer binds to the viral membrane through an ionic attraction, thus rendering the virus unable to infect host cells. Unfortunately, the extreme toxicity of these polymers has prevented their clinical use. Also, these polymers have a high molecular weight and are unable to pass through the renal membranes.
Attempts have been made to circumvent the toxicity and excretion problems by synthesis of low molecular weight (1,000 to 10,000) aliphatic polymers [R. M. Ottenbrite in "Biological Activities of Polymers", Amer. Chem. Soc. Symp. Ser., No. 182, pp. 205-220, eds. C. E. Carraher and C. G. Gebelein (1982)]. It has been found that such polymers are less toxic but have much reduced anti-viral activity. These low molecular weight aliphatic polymers may be classed as "random coil" polymers. Such polymers have an unpredictable configuration because of the flexibility of the backbone linking groups. The configuration of random coil polymers in solution may be generally described as globular. The reduced anti-viral activity of these random-coil polymers is believed to be due to a low binding affinity of the polymers with the viral membrane.
One approach to overcome the problems with the random-coil polymers would be to provide polymers which have rigid backbones with few degrees of freedom.
Certain chiral anionic oligomers which inhibit viral replication without the side effects shown by heparin and known polymers have now been found. These anionic oligomers have ordered anionic spacing, have a rigid backbone and are water-soluble. The anionic oligomers, as polydispersed mixtures, have been described in our copending U.S. patent application Ser. No. 710,370, filed Jun. 10, 1991, and corresponding PCT Application Serial No. PCT/US91/04804, filed Jul. 8, 1991, the disclosures of which are incorporated herein by reference. The anionic oligomers, as narrow poly- and mono-dispersed oligomers, have been described in U.S. patent application Ser. No. 818,753, filed Jan. 9, 1992, the disclosure of which is incorporated herein by reference.
Certain achiral anionic polyurea oligomers with rigid backbones and having few degrees of freedom have been described in a concurrently filed application.
Certain polythioureas have been disclosed for their anti-viral activity in Belgian Patent No. 544,868, issued Jul. 31, 1956.